Progress in the pathological arena of gynecological cancers

Abstract This review covers the significant new developments in the pathological classification of gynecological tumors. Many of these were included in the updated World Health Organization Classification of Female Genital Tract Tumours, published in 2020. Topics include the compelling evidence that a large majority of extrauterine high‐grade serous carcinomas arise from the fallopian tube; the Cancer Genome Atlas (TCGA) Classification of endometrial carcinomas; the discovery that most so‐called synchronous endometrial and ovarian endometrioid carcinomas represent metastasis from the endometrium to the ovary; and the division of cervical, vaginal, and vulval carcinomas into clinically meaningful HPV‐associated and HPV‐independent types. Newly described tumor types are covered, including endometrial and ovarian mesonephric‐like adenocarcinoma, uterine sarcoma types associated with specific molecular abnormalities, and gastric (gastrointestinal)‐type adenocarcinomas of the endometrium and vagina. Important molecular events in ovarian sex cord–stromal tumors are also discussed.


| INTRODUC TI ON
The updated 2020 World Health Organization (WHO 2020) Classification of Female Genital Tract Tumours (5th edition) was published online and in the traditional "Blue Book" in Autumn 2020. 1 The present review covers the significant developments and major changes in the classification of gynecological cancers, some of which emanate from the new WHO Classification. In a review such as this, most of the topics cannot be covered in detail and the reader is referred to the key references provided herein.

| WELL-E S TAB LIS HEDTUBALORIG IN OFMOS TE X TR AUTERINEHI G H -G R ADE S EROUSC ARCINOMA S
It is now well established that a significant majority of extrauterine (primary ovarian, tubal, or peritoneal) high-grade serous carcinomas (HGSC) arise from the distal fimbrial end of the fallopian tube from a precursor lesion known as STIC (serous tubal intraepithelial carcinoma). The evidence is compelling, both in sporadic cases and cases associated with germline BRCA mutations. [2][3][4][5] Unfortunately, this has not translated uniformly into clinical and pathological practice; in other words, the same extrauterine HGSC in a resection specimen DOI: 10.1002/ijgo.13871 could be categorized as of tubal, ovarian, or peritoneal origin by different pathologists. Although typically not important for management, this has obvious implications for epidemiological reasons and cancer registration and the tubal origin raises the possibility of prophylactic salpingectomy with ovarian preservation in premenopausal women at increased risk of the development of HGSC. Criteria for site assignment in extrauterine HGSC have been proposed [3][4][5] ( Table 1)

| NOE VIDEN CEFOR" FIELDEFFEC T "IN HIG H -G R ADES EROUSC ARCINOMA
It was previously thought that HGSC could arise at multiple independent sites through some form of "field effect." However, it has been convincingly shown that HGSC at different sites are clonal, with one site representing the primary and the others being metastatic. Almost all extrauterine HGSC exhibit TP53 mutation as an early founder event, and mutational analysis of ovarian and peritoneal HGSC with concurrent STIC has shown these to harbor identical TP53 mutations in the vast majority of cases. 7,8 The demonstration of an identical TP53 mutation in tumors at different sites is strong evidence for clonality, as the probability of an identical mutation occurring simultaneously at multiple sites is extremely low. It can be summarized that there is irrefutable evidence that almost all HGSC arises from a single tumor clone and that multiple foci of disease do not result from a multifocal origin or a field effect. 7,8 Similarly, it has been shown that cases of uterine serous carcinoma with involvement of the fallopian tube (even when confined to the tubal mucosa) mostly represent tubal metastases and not independent primary tubal lesions. 9

| THEC AN CERG ENOMEATL A S ( TCG A )MOLECUL ARCL A SS IFI C ATI ONOF ENDOME TRIALC ARCINOMA S
In 1983, in a seminal and widely cited paper, Bokhman proposed that there were two broad types of endometrial carcinoma, type I and type II. 10   POLE (ultramutated), microsatellite instability (MSI, hypermutated), copy-number low (also referred to as microsatellite stable or no specific molecular profile), and copy-number high (serous-like). It was demonstrated that the four molecular types are of prognostic significance, with POLE tumors having the best prognosis (even though they often look high grade morphologically) and copy-number high the worst. 12 Regarding the percentages of the four molecular types, copy-number low is the most prevalent accounting for approximately 39%, followed by MSI hypermutated (28%), copy-number high (26%), and POLE ultramutated (7%).
Since the delineation of the four molecular types and the demon-  rearrangements. [28][29][30][31][32] Predominantly these neoplasms were discovered using sophisticated molecular techniques, such as next generation sequencing, which have revealed novel diagnostic molecular events. Various other molecular abnormalities have also been reported in uterine sarcomas and with the increasing availability of these molecular techniques it is inevitable that additional "new" entities will be reported in the near future. This will result in diminution of the category of undifferentiated sarcoma.
These represent morphological variations rather than tumor types and, in practice, most pathologists did not use these categories, which suffered from lack of reproducibility and were of no prognostic significance. The 2020 WHO Classification categorizes cervical SCC into HPV-associated and HPV-independent types. 1 Table 2  intraepithelial lesion is absent. The 2020 WHO Classification also includes a category of SCC, not otherwise specified (NOS) to be used in settings where p16 staining or HPV testing is not available. 1

| CHANG E SINCL A SS IFIC ATI ONOF CERVIC ALG L ANDUL ARLE S IONS
Traditionally (including in WHO 2014), cervical adenocarcinomas were classified based on morphology and were divided into clinically meaningless and poorly reproducible categories with no biological basis, including villoglandular, endometrioid, and serous.
Analogous to cervical SCC, cervical adenocarcinomas are now categorized in WHO 2020 into HPV-associated and HPV-independent types ( Table 3). Most cervical adenocarcinomas are HPV-associated but a higher percentage than SCC (about 15%-20%) are HPVindependent. 34-39 HPV-independent cervical adenocarcinomas typically present at higher stage and have a worse prognosis. [34][35][36][37][38][39] The 2020 WHO Classification also divides adenocarcinoma precursor lesions into HPV-associated and HPV-independent types, the latter including gastric-type adenocarcinoma in situ and atypical lobular endocervical glandular hyperplasia. 1,40 HPV-associated adenocarcinomas are typified by easily identifiable mitotic figures and apoptotic bodies and almost always exhibit diffuse block-type immunoreactivity with p16. Subtypes of HPVassociated adenocarcinoma include usual type and mucinous type; the former encompasses villoglandular and micropapillary variants and mucinous type encompasses stratified mucin producing carcinoma, intestinal, signet ring, and NOS variants. 1,41 HPV-independent types of cervical adenocarcinoma are gastric type (the most common), mesonephric, and clear cell. [36][37][38][39] As discussed, these typically have a worse prognosis than HPV-associated adenocarcinomas and are almost always p16 negative or focally positive (nonblock-type immunoreactivity). Similarly in the vulva, traditional histologic typing of vulval SCC has been superseded by HPV status as the major determinant of classification. HPV-independent SCC have a worse prognosis with significantly worse recurrence-free and overall survival compared with HPV-associated SCC. [44][45][46][47][48] There is also growing evidence that HPV-independent SCC are less responsive to radiotherapy. 47 The majority of HPV-associated SCC exhibit basaloid or warty morphology, while HPV-independent SCC tend to be keratinizing; however, a significant percentage of cases (15%-20%) show overlapping morphologic features. While the nature of any adjacent precursor lesion may be useful in helping to determine the HPV status, in practice, ancillary testing (p16 or HPV testing) is necessary given the overlap in morphology. As in the cervix and vagina when HPV status cannot be confidently determined or resources are not available to undertake ancillary testing, a diagnosis of SCC NOS is acceptable, although this is not recommended. Most, but not all, HPV-independent vulval SCC are associated with TP53 mutations. 49 However, a proportion are TP53 wild type and there is growing evidence that these may have an intermediate prognosis between HPV-associated SCC (best prognosis) and HPV-independent TP53 mutated neoplasms (worst prognosis). 49 There have also been changes to the classification of primary vaginal adenocarcinomas with the description of new entities such as HPV-associated and gastric-type adenocarcinomas, 50

| NE WDE VELOPMENTSINOVARIAN S E XCORD-S TROMALTUMOR SAND MISCELL ANEOUSNEOPL A S MS
In WHO 2020, the classification of ovarian sex cord-stromal tumors is largely unchanged from the prior classification. 1 The category of gynandroblastoma (mixed sex cord-stromal tumor) has been reintroduced having been removed from the prior classification. This is one area of ovarian pathology where significant advances have been made in recent years. Sex cord-stromal tumors represent a heterogenous group of uncommon neoplasms that, when they exhibit classical morphology, are relatively easy to diagnose. However, there may be considerable morphological overlap between the different tumor types, and immunohistochemistry, while useful in confirming a sex cord-stromal tumor, is of minimal value in distinguishing between the different tumor types. Recent significant advances (see Table 4) include the demonstration that adult granulosa cell tumors contain somatic FOXL2 mutations in well over 90% of cases, 52 while a significant proportion of moderately and poorly differentiated Sertoli-Leydig cell tumors contain DICER1 mutations; these may be somatic or germline, the latter signifying DICER1 syndrome. 53,54 Ongoing studies are elucidating the molecular events in several other tumor types within the sex cordstromal category. For example, microcystic stromal tumor contains CTNNB1 or less frequently APC mutations and is occasionally an extracolonic manifestation of familial adenomatous polyposis. 55,56 In problematic cases, demonstration of the appropriate molecular abnormality assists in tumor classification.
Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT), which is included in the category of miscellaneous ovarian neoplasms in WHO 2020, has been shown to be characterized by deleterious germline or somatic mutations in a single gene SMARCA4 [57][58][59] in well over 90% of cases. SMARCA4 is part of the SWI/SNF complex, which is implicated in the pathogenesis of a growing number of other malignancies. Demonstration of this mutation and/or loss of immunohistochemical staining with SMARCA4 (BRG1) may, in the correct morphological context, be crucial in the diagnosis of this highly aggressive neoplasm. 60,61 It is recommended that all patients diagnosed with SCCOHT should be referred for germline SMARCA4 mutation testing. 62,63

CO N FLI C T SO FI NTE R E S T
The author has no conflicts of interest to declare.

AUTH O RCO NTR I B UTI O N S
The author is responsible for the design and writing of the paper.